In spite of the early discovery of insulin and its subsequent wide-spread use in the treatment of diabetes, and the later discovery and use of sulfonylureas (e.g. chlorpropamide, tolbutamide, acetohexamide, tolazamide) and biguanides (e.g. phenformin) as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin, necessary in a high percentage of diabetics where available synthetic hypoglycemic agents are not effective, requires multiple daily, usually self, injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in the urine or in the blood. The administration of an excessive dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Where effective, synthetic hypoglycemic agents are preferred over insulin, being more convenient to administer and less prone to cause severe hypoglycemic reactions. However, the clinically available hypoglycemics are fraught with other toxic manifestations which limit their use. In any event, where one of these agents may fail in an individual case, another may succeed. The need for additional hypoglycemic agents, which may be less toxic or succeed where others fail, is clearly evident.
In addition to the hypoglycemic agents cited above, a variety of other compounds have been reported to possess this type of activity, including 5-methylpyrazole-3-carboxylic acid [Smith, et al., J. Med. Chem. 8, 350 (1965)], 3-methylisoxazole-5-carboxylic acid [Dulin and Gerritsen, Proc. Soc. Expt. Biol. Med. 121, 777 (1966)], 1-methyl-4-(5-methyl-3-pyrazolyl)pyridinium iodide [Dulin et al., Proc. Soc. Expt. Biol. Med. 118, 499 (1965)], 1-methyl-4-(3-methyl-5-isoxazolyl)pyridinium chloride [Bauer et al., J. Med. Chem. 11, 984 (1968)], 2-carboxypyrazine [Dulin and Gerritsen, Metab. Clin. Exp. 18, 214 (1969)], a series of hexahydroindeno(1,2-c)pyrroles and dialkylaminomethylindans [Lahiri and Pathak, J. Pharm. Sci. 57, 1013 (1968)], methylenecyclopropylacetic acid and 4-pentenoic acid [Corredor et al., Proc. Nat. Acad. Sci. U.S. 58, 2299 (1967)].
A few of the compounds of the present invention have been previously disclosed. 4-Chloropyrrole-2-carboxylic acid, a compound of no known prior utility, has been described by Fringuelli et al. [Tetrahedron 25, 5815 (1969)]. The benzoyl (and substituted benzoyl) pyrrole carboxylic acids (IV, V, VI) of the present invention are generally disclosed by Belgian Pat. No. 870,910 as having uricosuric activity and thus useful in the treatment of gout and related pathological conditions. Certain compounds isomeric to those of the present invention have also been disclosed: 5-chloropyrrole-2-carboxylic acid [Fringuelli et al., loc. cit.; no known utility], 4-benzoylpyrrole-2-carboxylic acid [Groves et al., Can. J. Chem. 49, 2427 (1971); Sanchez et al., Carb. Res. 3, 486 (1967); generally disclosed to have uricosuric activity by Belgian Pat. No. 870,910; not active as hypoglycemic agents in the present case], 3-benzoylpyrrole-2-carboxylic acid [Kahn et al., Tetrahedron 22, 2095 (1966); generally disclosed to have uricosuric activity by Belgian Pat. No. 870,910], 5-phenylpyrrole-2-carboxylic acid [Blicke et al., J. Am. Chem. Soc. 66, 1675 (1944); no known utility] and 2-phenylpyrrole-3-carboxylic acid [Kondo and Suzuki, J. Pharm. Soc. Japan No. 544, 501 (1927); Chem. Abstr. 21, 3362; no known utility].
In some cases, methyl or ethyl esters or other homologs of the compounds of the present invention are known: methyl 4-benzoylpyrrole-3-carboxylate [Groves et al., Can. J. Chem. 51, 1089 (1973); no known utility], methyl 4-chloropyrrole-2-carboxylate [Fringuelli et al., loc. cit.; no known utility], and 5-benzoyl-1-methylpyrrole-2-acetic acids [including tolmetin, the p-methylbenzoyl analog; Carson et al., J. Med. Chem. 14, 646 (1971); which compounds are reported to have anti-inflammatory activity].